1 American Gastroenterological Association Institute Guidelines on the Role of Probiotics in the Management of Gastrointestinal Diseases Grace L. Su 1,2 , Cynthia W. Ko 3 , Premysl Bercik 4 ; Yngve Falck-Ytter 5,6 , Shahnaz Sultan 7 , Adam Weizman 8 , Rebecca Morgan 9 1 Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, U.S.A. Place, City, Country; 2 Gastroenterology Section, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, Michigan, USA; 3 Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA; 4 Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 5 Division of Gastroenterology, Case Western Reserve University, Cleveland, Ohio, USA; 6 Louis Stokes VA Medical Center, Cleveland, Ohio, USA; 7 Division of Gastroenterology, University of Minnesota, Minneapolis, MN, USA; 8 Division of Gastroenterology, Mount Sinai Hospital, Department of Medicine, University of Toronto; 9 Department Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON Acknowledgements: Clinical Guidelines Committee included Karen Chachu MD, PhD, Lukejohn Day MD, AGAF, Benjamin Lebwohl MD, AGAF, Thiruvengadam Muniraj MD, PhD, MRCP, Amit Patel MD, Anne F. Peery, MD Raj Shah, MD, Shahnaz Sultan, MD, Chair, Harminder Singh, MD, Siddharth Singh, MD, Stuart Spechler, MD, Grace Su, MD, Aaron P. Thrift, PhD Jennifer M. Weiss, MD and Adam V. Weizman, MD. This document presents the official recommendations of the American Gastroenterological Association (AGA) on the XX of XX. The guideline was developed by the AGA’s Clinical Practice Guideline Committee and approved by the AGA Governing Board. 1. Disclose conflicts of interest:
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American Gastroenterological Association Institute Guidelines on the Role of Probiotics in the Management of Gastrointestinal Diseases
Grace L. Su1,2, Cynthia W. Ko3, Premysl Bercik4; Yngve Falck-Ytter5,6, Shahnaz Sultan7, Adam Weizman8, Rebecca Morgan9
1 Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, U.S.A. Place, City, Country; 2 Gastroenterology Section, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, Michigan, USA; 3Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA; 4Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 5Division of Gastroenterology, Case Western Reserve University, Cleveland, Ohio, USA; 6Louis Stokes VA Medical Center, Cleveland, Ohio, USA; 7Division of Gastroenterology, University of Minnesota, Minneapolis, MN, USA; 8Division of Gastroenterology, Mount Sinai Hospital, Department of Medicine, University of Toronto; 9 Department Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON
Acknowledgements: Clinical Guidelines Committee included Karen Chachu MD,
PhD, Lukejohn Day MD, AGAF, Benjamin Lebwohl MD, AGAF, Thiruvengadam Muniraj MD, PhD,
MRCP, Amit Patel MD, Anne F. Peery, MD Raj Shah, MD, Shahnaz Sultan, MD,
Chair, Harminder Singh, MD, Siddharth Singh, MD, Stuart Spechler, MD, Grace Su, MD, Aaron P.
Thrift, PhD Jennifer M. Weiss, MD and Adam V. Weizman, MD.
This document presents the official recommendations of the American Gastroenterological Association
(AGA) on the XX of XX. The guideline was developed by the AGA’s Clinical Practice Guideline
Committee and approved by the AGA Governing Board.
1. Disclose conflicts of interest:
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Conflict of interest disclosure: All members were required to complete disclosure statement. These statements are maintained at the American Gastroenterological Association Institute (AGA) headquarters in Bethesda, Maryland and pertinent disclosure are published with the report.
Within the last twenty years, there has been an increasing recognition and interest in the role of the gut
microbiome in gastrointestinal health1. Defined by the Food and Agriculture Organization of the United
Nations and the World Health Organization as “live microorganisms which when administered in adequate
amounts confer a health benefit on the host”2, probiotics hold the promise of an effective way to alter the
microbiome for our benefit. Enthusiasm and popularity within the community for probiotics has led to a
multi-billion-dollar industry worldwide3. Because probiotics are not considered drugs in the United States
or Europe, the regulatory status is not the same as one which would normally accompany a pharmaceutical
product. The industry is largely unregulated and marketing of product is often geared directly at consumers
without providing direct and consistent proof of effectiveness4, 5. This has led to widespread use of
probiotics with confusing evidence for clinical efficacy. It is estimated that 3.9 million American adults
used some form of probiotics or prebiotics (nutrients which promote growth or beneficial functions of
beneficial microbes)6 in 2015, an amount which is four times that in 20077, 8. Given widespread use and
often biased sources of information, it is essential that clinicians have objective guidance for their patients
about the appropriate use of and indications for probiotics.
Although there has been a substantial number of studies examining probiotics in various gastrointestinal
diseases, the studies have been extremely varied including differences in the strain of microbe(s) used,
dose, and route of administration as well as the research methodology, including differences in the
reporting of endpoints and outcomes4. Furthermore, most of the studies with probiotics involved relatively
small number of patients compared to trials investigating the effects of pharmacological interventions.
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Conclusions drawn from meta-analyses or systematic reviews can be misleading if different studies with
different patient populations, different reported endpoints and outcomes or different strains or
combinations of probiotics are grouped together inappropriately2. Within species, different strains can
have widely different activities and biologic effects. Many immunologic, neurologic and biochemical
effects of gut microbiota are likely not only to be strain specific but also dose specific5. Furthermore,
combinations of different microbial strains may also have widely different activity as some microbial
activities are dependent on interactions between different strains. In developing this guideline, we have
examined the evidence presented in the accompanying technical review with these constraints in mind.
This guideline was developed utilizing a process previously outlined9. Briefly, the AGA process for
developing clinical practice guidelines follows the GRADE approach9 and best practices as outlined by
the National Academy of Science (formerly Institute of Medicine)10. A priori, the guideline development
panel and methodologist identified and formulated clinically relevant questions about the use of probiotic
formulations for the prevention and treatment of gastrointestinal diseases (not prebiotic use). Each
research question identified the population, intervention, comparison, and patient-important outcomes. A
technical review panel initially reviewed and assessed relevant systematic reviews that addressed the
clinical questions, updating high quality systematic reviews through December 2018 to inform the
recommendations when possible (Technical review, unpublished). For situations in which there was either
no recent systematic review available or the recent systematic review was not deemed high quality, the
technical review panel conducted the systematic review de novo. The findings from each systematic
review were assessed using the GRADE approach and presented in an evidence profile. The guideline
panel and the authors of the technical review met face-to-face on May 9, 2019 to discuss the findings from
the technical review and formulated these recommendations. Although the quality of evidence (Table 1)
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was a key factor in determining the strength of the recommendations (Table 2), the panel also considered
the balance between the benefits and harms of the interventions, as well as patients’ values and
preferences, resource use (i.e. cost), health equity, acceptability, and feasibility. The recommendations,
certainty of evidence, and strength of recommendations are summarized in Table 3. We hope to provide
clinicians with clear guidance regarding the appropriate use of specific probiotics in the context of specific
gastrointestinal diseases.
In addition, we were not able to assess the viability of each formulation reported in the studies as this
information was not routinely available. We recognize that different manufacturers use different
processes which may affect the actual content of the probiotic utilized but this is not within the scope of
this guideline and thus we provided the granular data regarding each strain as specified in the published
reports.
In patients with Clostridium difficile infection, we recommend the use of probiotics only in the context of
a clinical trial.
GRADE: No recommendation, knowledge gap
The AGA makes no recommendations for the use of probiotics in the treatment of Clostridium. difficile
(C. difficile) infection. Incidence of C. difficile infection is rising, being responsible for almost half a
million infections in the United States in 201111, with recurrences ofup to 19.9%, and leading to 29 000
deaths. Fecal microbiota transplantation is highly effective in treating recurrent C. difficile infection12, but
the data supporting the use of probiotics in initial or recurrent C. difficile infection are less convincing.
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The technical review identified five placebo-controlled RCTs evaluating probiotics as adjunct treatment
with antibiotics, testing four different probiotic formulations. The patient populations across studies
differed, including patients with an initial C. difficile infection, recurrent infection or both. Probiotics vs
placebo were administered together with metronidazole or vancomycin at low-dose or high-doses. Due to
these variations in the study design, as well as in clinical outcomes, data were deemed too heterogeneous
to be pooled in the analysis. All five published studies contained uncertain or high risk of bias regarding
blinding of outcome assessment and selective reporting.
The probiotic formulations studied included Saccharomyces boulardii (S. boulardii), Lactobacillus
plantarum (L. plantarum) 299v, Lactobacillus rhamnosus GG and the 4-strain combination of
Given the moderate-to-high quality evidence for reduction in all-cause mortality, severe NEC, days to
reach full enteral feeding, and days of hospitalization, we suggest using the two-genus combination of
Lactobacillus spp. and Bifidobacterium spp., B. animalis subsp. lactis, or L. reuteri over placebo or other
probiotics in premature infants.
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Summary
The gut microbiome plays an important role in gastrointestinal health and disease and probiotics represent
a promising modality for therapeutic intervention. The current evidence suggests that the use of certain
probiotic strains or probiotic strain combinations may prevent C. difficile infections for adults and children
on antibiotic treatment. However, the quality of evidence was low and the reporting of potential harms
was not always consistent. Thus, for patients who place a high value on avoidance of potential harms,
particularly those with severe illnesses or immunosuppression, it would be reasonable to select not to use
probiotics. While there was evidence for probiotics in the prevention of C. difficile, the technical review
found significant knowledge gap in the use of probiotics in treatment of C. difficile and recommend this
as an area for further study. Similar knowledge gaps exist in the use of probiotics in irritable bowel disease
and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). In the subset of patients with
pouchitis, current evidence supports the use of the eight-strain combination (L. casei, L. plantarum, L.
acidophilus, L. debrueckii subsp. bulgaricus, B. longum subsp. longum, B. breve, B. longum subsp.
infantis, and S. salivarius subsp. thermophilus) if feasibility of obtaining the combination is not an issue.
In preterm infants less than 36 weeks gestational age, the probiotic strains (B. animalis subsp. lactis or L.
reuteri) or combination of 2 strains (Lactobacillus spp. and Bifidobacterium spp.) may prevent the
development of NEC. For children with acute gastroenteritis in North America, however, the current
evidence does not support the use of probiotics.
We identified that significant knowledge gaps exist in this very promising and important area of research
due to the significant heterogeneity between studies and variability in the probiotic strains studied. The
lack of consistent harms reporting make it difficult to assess true harms. The lack of product
manufacturing details prohibits true comparisons and decreases the feasibility of obtaining certain
products by patients. Future high-quality studies are urgently needed which address these pitfalls.
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Table 1: Quality of Evidence
High We are very confident that the true effect lies close to that of the estimate of the effect. Moderate We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the
effect, but there is a possibility that it is substantially different. Low Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate
of the effect. Very Low
We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect
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Table 2: Strength of Recommendation
For the Patient For the Clinician
Strong Most individuals in this situation would want the recommended course of action and only a small proportion would not.
Most individuals should receive the recommended course of action. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.
Conditional The majority of individuals in this situation would want the suggested course of action, but many would not.
Different choices will be appropriate for different patients. Decision aids may be useful in helping individuals in making decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working towards a decision.
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Table 3: Summary of recommendations: Recommendations Strength of
Recommendation Quality of Evidence
1. In patients with C. difficile infection, we recommend the use of probiotics only in the context of a clinical trial.
No recommendation Knowledge gap
2. In adults and children on antibiotic treatment, we suggest the use of S. boulardii; or the two-strain combination of L. acidophilus and L. casei; or the three-strain combination of L. acidophilus, L. delbruekii subsp. bulgaricus, and B. bifidum; or the four-strain combination of L. acidophilus, L. delbruekii subsp. bulgaricus, B. bifidum, and S. thermophilus over no or other probiotics for prevention of C. difficile infection. Comment: Patients who place a high value on the potential harms (particularly those with severe illnesses) or a high value on avoiding the associated cost and a low value on the small risk of C. difficile development (particularly in the outpatient setting), would reasonably select no probiotics.
Conditional Low
3. In patients with Crohn’s disease, we recommend the use of probiotics only in the context of a clinical trial.
No recommendation Knowledge gap
4. In patients with ulcerative colitis, we recommend the use of probiotics only in the context of a clinical trial.
No recommendation Knowledge gap
5. In patients with pouchitis, we suggest the use of L. casei, L. plantarum, L. acidophilus, L. debrueckii subsp. bulgaricus, B. longum subsp. longum, B. breve, B. longum subsp. infantis, and S. salivarius subsp. thermophilus over no or other probiotics. Comment: Patients for whom the feasibility and cost of using this combination of bacterial strain is problematic may reasonably select no probiotics.
Conditional Very low
6. In symptomatic children and adults with irritable bowel syndrome, we recommend the use of probiotics only in the context of a clinical trial.
No recommendations Knowledge gap
7. In children with acute infectious gastroenteritis, we suggest against the use of probiotics. Conditional Moderate
8. In preterm infants (less than 36 weeks GA), we suggest using Lactobacillus spp. and Bifidobacterium spp. or B. lactis or L. reuteri for prevention of NEC over no and other probiotics.
Conditional Moderate/high
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